New Anticoagulants: When and Why Should I Use Them? Christine L. - - PDF document

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New Anticoagulants: When and Why Should I Use Them? Christine L. - - PDF document

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Winship Cancer Institute of Emory University New Anticoagulants: When and Why Should I Use Them? Christine L. Kempton, MD, MSc Associate Professor of Pediatrics and Hematology and Medical Oncology Hemophilia of Georgia, Inc , Directors Chair in

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1 Winship Cancer Institute of Emory University

New Anticoagulants: When and Why Should I Use Them?

Christine L. Kempton, MD, MSc Associate Professor of Pediatrics and Hematology and Medical Oncology Hemophilia of Georgia, Inc , Directors Chair in Hemostasis

Disclosures

  • Nothing relevant to disclose.
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Venous Thromboembolism (VTE)

  • Overall annual incidence 1/1000 persons
  • Increases with age: 5/1000 persons annually in people over 80

years of age

  • Location
  • Pulmonary embolism (PE) – 2/3
  • Deep venous thrombosis (DVT) – 2/3
  • Mortality within one month of diagnosis:
  • DVT – 6%
  • PE – 12%
  • Long-term complications
  • DVT- post-thrombotic syndrome occurs in 20-50%
  • PE- chronic pulmonary hypertension occurs in 2-4%

Yeh et al. Blood 2014 pre-published

Old Oral Anticoagulants: Warfarin

  • First approved for medical use in 1954
  • Inhibits vitamin K reductase (VKOR)
  • Prevents carboxylation of clotting factors II, VII, IX, and X
  • Partially decarboxylated proteins have less clotting activity
  • Metabolised by cytochrome P450 (CYP)
  • particularly CYP2C9
  • Limitations:
  • Food-drug interactions
  • Drug-drug interactions
  • Delayed onset of action
  • Variability of response monitoring
  • Safety and efficacy dependent on therapeutic INR

Hirsh et al. Circulation 2003; 107: 1692-1711

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Factor IXa Factor VIIIa Factor XIa Fibrinogen Factor IX Factor Xa Factor Va Thrombin Prothrombin Fibrin Factor X

4 Rivaroxaban Apixiban Edoxaban Dabigitran

Factor VIIa Tissue Factor

Novel Oral Anticoagulants (NOAC)

Dabigitran Rivaroxaban Apixiban Edoxaban

Target Thrombin Factor Xa Factor Xa Factor Xa Pro-drug Yes No No No Elimination half-life 14-17 hrs 7-11 hrs 8-14 hrs 5-11 hrs Bioavailability % 3-7 80 66 45 Protein Binding % 35 >90 ~85 40-59 Route of elimination Urine ~80%, feces ~20% Urine ~66%, feces ~30% Urine ~25%, feces ~70% Urine ~35% Feces ~60% Dosing Twice/day Once/day* Twice/day Once/day Substrate of CYP enzymes No Yes (CYP3A4, CYP2J2) Yes (CYP3A4) Yes (CYP3A4) Substrate of P-glycoprotein Yes Yes Yes Yes

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Indications for Use

Non- valvular

  • A. Fib

VTE prevention Initial VTE Treatment VTE Secondary Prevention

Dabigitran +

  • + (after 5-10 days
  • f parenteral AC)

+ Rivaroxaban + + + + Apixiban + + * * Edoxaban *

  • *(after 5-10 days of

parenteral AC)

*

*FDA application pending

Treatment of Acute VTE: Efficacy

VTE Recurrence HR (95% CI) NOAC Warfarin

Dabigitran- RE-COVER Study1; n=1274 2.4% 2.1% 1.10 (0.65-1.84) Rivaroxaban-EINSTEIN Study2; n=3449 2.1% 3.0% 0.68 (0.44-1.04) Rivaroxaban-EINSTEIN PE Study3; n=4832 2.1% 1.8% 1.12 (0.75-1.68) Apixiban-AMPLIFY Study4; n=5244 2.3% 2.7% 0.84 (0.60-1.18) Edoxaban-Hokusai-VTE Study5; n=4921 3.2% 3.5% 0.89 (0.70-1.13)

  • 1. Schulman et al. NEJM. 2009;361:2342-52
  • 2. EINSTEIN Investigators. NEJM 2010;363:2499-510
  • 3. EINSTEIN PE Investigators NEJM 2012;366:1287-97
  • 4. Agnelli et al. NEJM 2013; 1369:799-808
  • 5. Houkusai VTE Investigators. NEJM 2013;369:1406-15
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Treatment of Acute VTE: Safety

Major Bleeding Clinically Relevant Non-Major Bleeding NOAC Warfarin HR (95% CI) NOAC Warfarin HR (95% CI) Dabigitran- RE-COVER Study1; n=1274 1.6% 1.9% 0.82 (0.45- 1.48) 4.0% 7.8%

  • Rivaroxaban-EINSTEIN

Study2; n=3449 1.8% 1.2% 0.65 (0.33- 1.30) 7.3% 7.0%

  • Rivaroxaban-EINSTEIN PE

Study3; n=4832 1.1% 2.2% 0.49 (0.31- 0.79) 9.5% 9.8%

  • Apixiban-AMPLIFY study4;

n=5244 0.6% 1.8% 0.31* (0.17- 0.55) 3.8% 8.0% 0.48 (0.38-0.60) Edoxaban-Hokusai-VTE study5; n=4921 1.4% 1.6% 0.84 (0.59- 1.21) 8.1% 8.6%

  • *p <0.001
  • 1. Schulman et al. NEJM. 2009;361:2342-52
  • 2. EINSTEIN Investigators. NEJM 2010;363:2499-510
  • 3. EINSTEIN PE Investigators NEJM 2012;366:1287-97
  • 4. Agnelli et al. NEJM 2013; 1369:799-808
  • 5. Houkusai VTE Investigators. NEJM 2013;369:1406-15

Dabigitran Rivaroxaban Apixiban Dabigitran Rivaroxaban Apixiban

Dentali F, Circulation 2012;126:2381-2391

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Secondary Prevention of VTE: Efficacy

VTE Recurrence HR (95% CI) NOAC Placebo

Dabigitran-RE-MEDY & RE-SONATE1; n=2856

1.8% 5.6%* 0.08 (0.02-0.25)

Rivaroxaban-EINSTEIN Study2 n=1196

1.3% 7.1% 0.18 (0.09-0.39)

Apixiban-AMPLIFY EXT3; 2.5mg n=2482

1.7%^ 8.8% 0.19 (0.11-0.33) *Warfarin treated group1.3%, HR 1.44 (95% CI 0.78-2.64) ^Apixiban 2.5 mg and 5.0 mg similar

1. Schulman et al. 2013;368:709-18 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. Agnelli et al. NEJM 2013; 1369:799-808

Secondary Prevention of VTE: Safety

Major Bleeding Clinically Relevant Non-Major Bleeding NOAC Place bo HR (95% CI) NOAC Placebo HR (95% CI)

Dabigitran-RE-MEDY & RE-SONATE1; n=2856

0.9%

  • 5.0%

1.8% 2.92 (1.52- 5.60)

Rivaroxaban- EINSTEIN Study2 n=1196

0.7%

  • 5.4%

1.2%

  • Apixiban-AMPLIFY

EXT3; 2.5mg n=2482

0.2% 0.5% 0.49 (0.09- 2.64) 3.0% 2.3% 1.29** (0.72-2.33)

^Apixiban 2.5 mg and 5.0 mg similar

1. Schulman et al. 2013;368:709-18 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. Agnelli et al. NEJM 2013; 1369:799-808

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Agnelli et al. NEJM 2013; 1369:799-808

Patient Selection

Use Avoided:

  • PE with hemodynamic

instability

  • Significant risk of bleeding
  • Recent trauma or surgery
  • CrCl < 30 ml/min
  • Hepatic dysfunction (Child-

Pugh B)

  • Pregnancy
  • Active cancer
  • High-risk settings such as HIT
  • r antiphospholipid syndrome
  • Concurrent use of :
  • Strong inhibitors/inducers of

CYP3A4 and P-glycoprotein

Use with Caution:

  • Advanced age > 75 years
  • Extremes of weight < 60 or >

150 kg

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INR Control Good Poor Good Poor Lifestyle burden Low High May benefit Limited benefit No benefit May benefit Adherence

Patients Currently on Warfarin NOAC Selection

  • Preference for once daily vs. twice daily dosing: Favors

rivaroxaban and edoxaban

  • Rivaroxaban should be taken with food
  • Ability to use an all oral regimen at diagnosis: Favors

rivaroxaban and apixiban

  • Low renal clearance- Avoid dabigitran and favor apixiban
  • History of coronary artery disease—Avoid dabigitran
  • Upper GI complaints - Avoid dabigitran
  • Recent GI bleed- Favors apixiban
  • Clinical setting is extended treatment for secondary

prevention—Favors apixiban

  • CYP3A4 interaction-Favors dabigitran
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Monitoring

  • Acute Treatment:
  • Early follow-up if discharged from the ED
  • Follow-up at times of transition (apixiban: 7 days, rivaroxaban: 21

days)

  • Extended Treatment
  • Follow-up to assess adherence, efficacy, side effects, stability of

renal/liver function

  • Every 3-12 months, depending on renal function
  • Laboratory monitoring
  • Approved kits for rivaroxaban (anti-Xa assay) and dabigitran (anti-IIa

assay)

  • Not recommended for routine monitoring
  • Potential uses:
  • Emergent surgery or other invasive procedure
  • Failure of efficacy or safety
  • Anticipated alterations of pharmacokinetics or pharmacodynamics

Practical Issues

  • Switching from warfarin to NOAC:
  • Stop warfarin and start NOAC when INR < 2.0
  • Likely after 2-3 missed doses depending on the INR at cessation of

warfarin

  • Encourage use of Medic Alert that identifies NOAC use
  • Discuss importance of adherence:
  • Use of pill box essential
  • Take at similar time each day
  • Missed dose:
  • < 12 hours (daily dosing) and 6 hours (BID dosing) from missed

dose, then take dose

  • > 12 hours (daily dosing) and 6 hours (BID dosing) from missed

dose—skip the dose

  • Do not double up
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Bleeding Management

  • No reversal agent currently available, but new agents are in

development

Factor Xa inhibitors Direct Thrombin Inhibitors Normalization of hemostasis 12-24h CrCl > 80 mL/min: 12-24h CrCl 50-80 mL/min: 24-36h CrCl 30-50 mL/min: 36-48h CrCl < 30 mL/min: > 48h General measures Hold medication, local hemostatic measures, transfusion therapy as need for anemia and thrombocytopenia, tranexamic acid Increase clearance

  • Hemodialysis

Promote hemostasis Prothrombin complex concentrates (PCC) (25 U/kg), activated PCC (aPCC) (50 U/kg), or rFVIIa (90 mcg/kg)-no clinical data

Heidbuchel et al. Eur Heart J 2014 pre-published

Peri-operative Management

  • Post-operative
  • Restart NOAC once full anticoagulation is allowed—likely 48-72 hours after

major surgery

  • May need prophylactic anticoagulation with LWMH in the immediate post-
  • perative period until able to resume full dose anticoagulation
  • Pre-operative: Low vs. high surgical bleeding risk

Dabigitran Apixiban Edoxaban Rivaroxaban Low High Low High Low High Low High CrCl > 80 mL/min > 24h > 48h > 24 h > 48h ND ND > 24 h > 48h CrCl 50-80 mL/min > 36h > 72h > 24 h > 48h ND ND > 24 h > 48h CrCl 30-50 mL/min > 72h > 120h > 24 h > 48h ND ND > 24 h > 48h

ND=no data

Heidbuchel et al. Eur Heart J 2014 pre-published Prescribing information

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Summary

  • New oral anticoagulants …
  • offer a real alternative to warfarin therapy for a large number of

patients.

  • are efficacious for:
  • Treatment of acute VTE: DVT and hemodynamically stable PE.
  • Secondary prevention of recurrent VTE.
  • are as safe or safer than warfarin.
  • are more convenient and less burdensome than warfarin.
  • Patients not appropriate for NOACs include those with:
  • Severe renal or liver impairment
  • Cancer
  • Extremes of weight
  • Pregnant
  • Significantly advanced age
  • Strong CYP3A4 and P-gp inhibitors